Blood flow reprograms lymphatic vessels to blood vessels
Chiu-Yu Chen, … , Guillermo Oliver, Mark L. Kahn
Chiu-Yu Chen, … , Guillermo Oliver, Mark L. Kahn
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):2006-2017. https://doi.org/10.1172/JCI57513.
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Research Article Vascular biology

Blood flow reprograms lymphatic vessels to blood vessels

Abstract

Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain–containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate–specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.

Authors

Chiu-Yu Chen, Cara Bertozzi, Zhiying Zou, Lijun Yuan, John S. Lee, MinMin Lu, Stan J. Stachelek, Sathish Srinivasan, Lili Guo, Andres Vincente, Patricia Mericko, Robert J. Levy, Taija Makinen, Guillermo Oliver, Mark L. Kahn

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Figure 3

Mesenteric SVs in adult Vav-Cre;Slp76fl/– mice lose lymphatic identity and acquire venous identity.

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Mesenteric SVs in adult Vav-Cre;Slp76fl/– mice lose lymphatic identity a...
(A) Mesenteric SVs that form in Vav-Cre;Slp76fl/– mice lose expression of lymphatic molecular markers and acquire expression of the blood vessel marker vWF and venous marker EPHB4 but not the arterial marker CX40. Scale bars: 50 μm. (B) Model of vascular remodeling in SLP76-deficient mice. Shown are the vascular anatomy and flow through the intestinal and mesenteric vessels of neonatal wild-type, neonatal Slp76–/– (KO neonate), and mature Slp76–/– (KO adult) animals. SLP76-deficient radiation chimeras (KO chimera) develop a vascular phenotype like that observed in KO neonates. In the wild-type animal, afferent mesenteric blood flow is carried by the mesenteric artery (A, red), while efferent blood and lymph are carried by the mesenteric vein (V, blue) and lymphatic (L, green), respectively. In the KO neonate or KO chimera, blood-lymphatic mixing allows blood to enter the mesenteric lymphatics, but flow is minimal, and lymphatic identity is preserved. In the KO adult, mesenteric lymphatics become incorporated into an arterio-venous shunt that directs efferent blood flow through them (right), a process that produces an SV (blue) with blood vessel identity. Histologic studies reveal the presence of small lymphatic vessels that retain lymphatic identity in mature KO animals.